The major focus of the Geriatric Psychiatry Branch (GPB) is the study of individuals with memory disorders as a result of age or neurodegeneration. In particular, memory is the most important earliest clinical symptom of Alzheimer?s disease (AD). Although the hippocampus may not be a biological determinant of all memories, there is a growing body of evidence suggesting that dysfunction of the hippocampus plays an important role in the most common forms of memory disorders. Also, there is evidence that the cholinergic system has an important role in normal memory, at least in part through its influence on hippocampal function, in age-related memory loss, and in AD. Medications designed to enhance the cholinergic system through increasing concentrations of the neurotransmitter acetylcholine in the synapse are the only approved drugs for the treatment of AD. The Neuroimaging Section of GPB has been using magnetic resonance imaging (MRI) to study the hippocampus and positron emission tomography (PET) to study the cholinergic system. MRI Studies: The study of longitudinal changes in hippocampal structure and function should allow us to understand the contributions that various genotypes, e.g., ApoE4, and abnormalities in cerebrospinal fluid, e.g., Ab42 and tau, play in the development of abnormal hippocampal structure and function. Thus, GPB has protocols in place for genotype determination, cognitive testing, cerebrospinal fluid assessment and neuroimaging studies of the structure of the brain with magnetic resonance imaging (MRI) and of the cholinergic system using positron emission tomography (PET). The specific objective of our first project was to determine whether the presence of a single e4 allele of the Apolipoprotein E gene, an allele known to increase susceptibility to Alzheimer?s disease is associated with an increased rate of hippocampal volume loss and/or decline in cognition in healthy women in their sixth decade. Nine APOE e4- (60.6 ? 10.2 yrs old) and 16 APOE e4+ (55.1 ? 6.0 yrs) healthy women underwent neurocognitive testing and an MRI scan at their time of entry into the study (baseline) and two years later. Hippocampal volume determinations were based on manual outlining of sagittal slices aided by axial, coronal and 3D views of high-resolution 124-slice whole brain scans obtained from a 1.5T scanner using a T1-weighted 3D gradient echo sequence with RF spoiling (TR/TE/flip angle; 24msec/3msec/30o). The percent change in hippocampal volume per year was significantly greater in the APOE e4+ group (2.32 ? 1.75 %) than in the APOE e4- group (0.77 ? 1.02 %, t = 2.41, p < .03, 2-tailed). There were no significant differences between the APOE e4+ and APOE e4- groups on any of the cognitive measures, and hippocampal volume loss was not correlated with changes in any of the above cognitive measures. We concluded that the presence of a single APOE e4 allele is associated with an increased rate of hippocampal volume loss in healthy women in their sixth decade of life that is not related to any detectable memory changes. PET Studies: Because, the precise effects of normal aging on the cholinergic system are unknown as both in vitro and PET studies have shown conflicting results, our first specific objectives were to determine whether we could accurately and reliably measure attributes of the cholinergic system in regions of the brain of awake humans with PET, and whether we could establish if there were any changes in these attributes as individuals age. Previous in vitro and in vivo work with the F-18 labeled muscarinic agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (18F P-TZTP) suggested the use of 18FP-TZTP to selectively quantify M2 receptors in humans. In this study, we used 18FP-TZTP, to infer M2 receptor avidity in the brains of 15 healthy younger subjects (mean age = 28.3 ? 5.5 y) and 20 healthy older subjects (mean age = 62.1? 7.7 y). Corrections for subject motion during the 120 min acquisition and partial voluming (PVC) were performed. A one-tissue compartment model was used to estimate the volumes of distribution (VT) of 18FP-TZTP. Within both groups of subjects, volumes of distribution (K1/k2) in cortical, subcortical, and cerebellar areas were consistent with M2 receptor topography. Compared to younger subjects older subjects had significantly higher means and standard deviations for the volumes of distribution of 18FP-TZTP throughout much of the cerebellum, cortex and subcortex (Global Gray VT = 742 ? 163 in older subjects and 645 ? 74 in younger subjects, p < 0.03). Across all subjects 18FP-TZTP, regional and Global Gray distribution volumes were significantly correlated to age (Global Gray VT, r = 0.41, p < .01). A lower concentration of acetylcholine in the synapse of some older subjects is one possible explanation of the data.